Neuromuscular disease genetics in underrepresented populations : increasing data diversity

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dc.contributor.author Wilson, Lindsay A.
dc.contributor.author Macken, William L.
dc.contributor.author Perry, Luke D.
dc.contributor.author Record, Christopher J.
dc.contributor.author Schon, Katherine R.
dc.contributor.author Frezatti, Rodrigo S.S.
dc.contributor.author Raga, Sharika
dc.contributor.author Naidu, Kireshnee
dc.contributor.author Köken, Ozlem Yayıcı
dc.contributor.author Kapapa, Musambo M.
dc.contributor.author Dominik, Natalia
dc.contributor.author Efthymiou, Stephanie
dc.contributor.author Morsy, Heba
dc.contributor.author Nel, Melissa
dc.contributor.author Fassad, Mahmoud R.
dc.contributor.author Gao, Fei
dc.contributor.author Patel, Krutik
dc.contributor.author Schoonen, Maryke
dc.contributor.author Bisschoff, Michelle
dc.contributor.author Vorster, Armand
dc.contributor.author Jonvik, Hallgeir
dc.contributor.author Human, Ronel
dc.contributor.author Lubbe, Elsabeth (Elsa)
dc.contributor.author Nonyane, Malebo
dc.contributor.author Vengalil, Seena
dc.contributor.author Nashi, Saraswati
dc.contributor.author Srivastava, Kosha
dc.contributor.author Lemmers, Richard J.L.F.
dc.contributor.author Reyaz, Alisha
dc.contributor.author Mishra, Rinkle
dc.contributor.author Topf, Ana
dc.contributor.author Trainor, Christina I.
dc.contributor.author Steyn, Elizabeth C.
dc.contributor.author Mahungu, Amokelani C.
dc.contributor.author Van der Vliet, Patrick J.
dc.contributor.author Ceylan, Ahmet Cevdet
dc.contributor.author Hiz, A. Semra
dc.contributor.author Cavdarlı, Bussranur
dc.contributor.author Gunduz, C. Nur Semerci
dc.contributor.author Ceylan, Gulay Gulec
dc.contributor.author Nagappa, Madhu
dc.contributor.author Tallapaka, Karthik B.
dc.contributor.author Govindaraj, Periyasamy
dc.contributor.author Van der Maarel, Silvere M.
dc.contributor.author Narayanappa, Gayathri
dc.contributor.author Nandeesh, Bevinahalli N.
dc.contributor.author Somwe, Wa Somwe
dc.contributor.author Bearden, David R.
dc.contributor.author Kvalsund, Michelle P.
dc.contributor.author Ramdharry, Gita M.
dc.contributor.author Oktay, Yavuz
dc.contributor.author Yis, Uluc
dc.contributor.author Topaloglu, Haluk
dc.contributor.author Sarkozy, Anna
dc.contributor.author Bugiardini, Enrico
dc.contributor.author Henning, Franclo
dc.contributor.author Wilmshurst, Jo M.
dc.contributor.author Heckmann, Jeannine M.
dc.contributor.author McFarland, Robert
dc.contributor.author Taylor, Robert W.
dc.contributor.author Smuts, Izelle
dc.contributor.author Van der Westhuizen, Francois H.
dc.contributor.author Da Rosa Sobreira, Claudia Ferreira
dc.contributor.author Tomaselli, Pedro J.
dc.contributor.author Marques Jr, Wilson
dc.contributor.author Bhatia, Rohit
dc.contributor.author Dalal, Ashwin
dc.contributor.author Srivastava, M.V. Padma
dc.contributor.author Yareeda, Sireesha
dc.contributor.author Nalini, Atchayaram
dc.contributor.author Vishnu, Venugopalan Y.
dc.contributor.author Thangaraj, Kumarasamy
dc.contributor.author Straub, Volker
dc.contributor.author Horvath, Rita
dc.contributor.author Chinnery, Patrick F.
dc.contributor.author Pitceathly, Robert D.S.
dc.contributor.author Muntoni, Francesco
dc.contributor.author Houlden, Henry
dc.contributor.author Vandrovcova, Jana
dc.contributor.author Reilly, Mary M.
dc.contributor.author Hanna, Michael G.
dc.date.accessioned 2024-10-15T09:58:37Z
dc.date.available 2024-10-15T09:58:37Z
dc.date.issued 2023-07
dc.description DATA AVAILABILITY : At the end of the study, participants de-identified exome and genome data will be archived in the European Molecular Biology Laboratory European Bioinformatics Institute’s European Genome-Phenome Archive (EMBL EBI EGA), with community access to this and selected de-identified REDCap data managed via an ICGNMD Data Access Committee. en_US
dc.description.abstract Neuromuscular diseases (NMDs) affect ∼15 million people globally. In high income settings DNA-based diagnosis has transformed care pathways and led to gene-specific therapies. However, most affected families are in low-to-middle income countries (LMICs) with limited access to DNA-based diagnosis. Most (86%) published genetic data is derived from European ancestry. This marked genetic data inequality hampers understanding of genetic diversity and hinders accurate genetic diagnosis in all income settings. We developed a cloud-based transcontinental partnership to build diverse, deeply-phenotyped and genetically characterized cohorts to improve genetic architecture knowledge, and potentially advance diagnosis and clinical management. We connected 18 centres in Brazil, India, South Africa, Turkey, Zambia, Netherlands and the UK. We co-developed a cloud-based data solution and trained 17 international neurology fellows in clinical genomic data interpretation. Single gene and whole exome data were analysed via a bespoke bioinformatics pipeline and reviewed alongside clinical and phenotypic data in global webinars to inform genetic outcome decisions. We recruited 6001 participants in the first 43 months. Initial genetic analyses 'solved' or 'possibly solved' ∼56% probands overall. In-depth genetic data review of the four commonest clinical categories (limb girdle muscular dystrophy, inherited peripheral neuropathies, congenital myopathy/muscular dystrophies and Duchenne/Becker muscular dystrophy) delivered a ∼59% 'solved' and ∼13% 'possibly solved' outcome. Almost 29% of disease causing variants were novel, increasing diverse pathogenic variant knowledge. Unsolved participants represent a new discovery cohort. The dataset provides a large resource from under-represented populations for genetic and translational research. In conclusion, we established a remote transcontinental partnership to assess genetic architecture of NMDs across diverse populations. It supported DNA-based diagnosis, potentially enabling genetic counselling, care pathways and eligibility for gene-specific trials. Similar virtual partnerships could be adopted by other areas of global genomic neurological practice to reduce genetic data inequality and benefit patients globally. en_US
dc.description.department Paediatrics and Child Health en_US
dc.description.librarian am2024 en_US
dc.description.sdg SDG-03:Good heatlh and well-being en_US
dc.description.sponsorship This work was supported by a Medical Research Council strategic award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) MR/S005021/1. Additional ICGNMD support including travel and subsistence costs was received from the National Brain Appeal (UK Charity 290173) and University College London Global Engagement Funds. Fellowships for R.S.S.F. and K.N. were funded by the Guarantors of Brain (UK Charity 1197319). The authors acknowledge and are grateful for: conference bursaries from the World Muscle Society to R.S.S.F. S.R., K.N., O.Y.K., P.J.T., V.V.Y. S.V.D.M. and R.L. are members of the European Reference Network for Rare Neuromuscular Diseases (ERN EURO-MND). M.P.K.: National Institute of Neurological Disorders and Stroke (1K23NS112463), American Association of Neuromuscular & Electrodiagnostic Medicine Development Award and Allen Foundation. D.B.: National Institute of Neurological Disorders and Stroke (K23NS117310) and support from Biogen for the KCTN1 Natural History Study. G.M.R.: University College London and UCLH Biomedical Research Centre funding, Health Education England and University College London Hospitals NHS Foundation Trust Innovation Fund. R.M.F., R.W.T. and K.P.: Wellcome core support (203105/Z/16/Z). R.M.F. received additional support from the Lily Foundation and the Leigh Syndrome International Consortium. A.T.: EU Horizon 2020 research and innovation Solve-RD project, No. 779257. F.H.W., M.S., M.B. and A.V.: South African Medical Research Council award ‘The genetics of Neuromuscular Diseases in South African patient populations: the ICGNMD study’. K.T. is funded by a J. C. Bose Fellowship, Science and Engineering Research Board (SERB) Department of Science and Technology, India. P.G. is supported by the Centre for DNA Fingerprinting and Diagnostics (CDFD) Core Research Grant, Department of Biotechnology, Government of India. R.H.: Wellcome award 109915/Z/15/Z, UK Medical Research Council award MR/N025431/1, the Lily Foundation, Evelyn Trust Research Grant (Ref 19/14), Action for A-T and UK Research and Innovation Newton Fund (MR/NO27302/1). P.F.C.: Wellcome awards 212219/Z/18/Z and 224486/Z/21/Z, UK Medical Research Council awards MC_PC_21046, MR/S035699/1 and MR/ S01165X/1, LifeArc Philanthropic Fund, NIHR BioResource for Translational Research in Common and Rare Diseases, Alzheimer’s Society, NIHR BioResource for Genes and Cognition and Leverhulme Trust. R.D.S.P.: UK Medical Research Council MR/ S002065/1 and MC_PC_21046, and the Lily Foundation. H.H.: UK Medical Research Council, Wellcome, UCLH Biomedical Research Centre (NIHR-BRC), Rosetrees Trust, and SOLVE-RD. M.M.R.: Wellcome grant G104817, National Institute of Neurological Disorders and Stroke and Office of Rare Diseases grants U54NS065712 and 1UOINS109403-01 and Muscular Dystrophy Association grant. en_US
dc.description.uri https://www.edusoft.ro/brain/index.php/brain en_US
dc.identifier.citation Wilson, L.A., Macken, W.L., Oerry, D. et al. 2023, 'Neuromuscular disease genetics in underrepresented populations : increasing data diversity', Brain, vol. 146, pp. 5098-5109. https://DOI.org/10.1093/brain/awad254. en_US
dc.identifier.issn 2068-0473 (print)
dc.identifier.issn 2067-3957 (online)
dc.identifier.other 10.1093/brain/awad254
dc.identifier.uri http://hdl.handle.net/2263/98595
dc.language.iso en en_US
dc.publisher Oxford University Press en_US
dc.rights © The Author(s) 2023. This is an Open Access article distributed under the terms of the Creative Commons Attribution License. en_US
dc.subject Neuromuscular diseases (NMDs) en_US
dc.subject Diagnosis en_US
dc.subject Therapies en_US
dc.subject Deoxyribonucleic acid (DNA) en_US
dc.subject SDG-03: Good health and well-being en_US
dc.title Neuromuscular disease genetics in underrepresented populations : increasing data diversity en_US
dc.type Article en_US


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